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New Roles for Nuclear Receptors in Prostate Cancer

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New Roles for Nuclear Receptors in Prostate Cancer 2311 D A Leach et al. Nuclear receptors in 23:11 T85–T108 Thematic Review prostate cancer WOMEN IN CANCER THEMATIC REVIEW New roles for nuclear receptors in prostate cancer Correspondence should be addressed Damien A Leach, Sue M Powell and Charlotte L Bevan to C L Bevan Email Division of Cancer, Imperial Centre for Translational & Experimental Medicine, Imperial College London, charlotte.bevan@imperial. Hammersmith Hospital Campus, London, UK ac.uk Abstract Prostate cancer has, for decades, been treated by inhibiting androgen signalling. This Key Words is effective in the majority of patients, but inevitably resistance develops and patients f androgen receptor progress to life-threatening metastatic disease – hence the quest for new effective f endocrine therapy therapies for ‘castrate-resistant’ prostate cancer (CRPC). Studies into what pathways resistance can drive tumour recurrence under these conditions has identified several other nuclear f estrogen receptor receptor signalling pathways as potential drivers or modulators of CRPC. f gene transcription The nuclear receptors constitute a large (48 members) superfamily of transcription factors f prostate sharing a common modular functional structure. Many of them are activated by the f coactivator binding of small lipophilic molecules, making them potentially druggable. Even those for f corepressor which no ligand exists or has yet been identified may be tractable to activity modulation by small molecules. Moreover, genomic studies have shown that in models of CRPC, other Endocrine-Related Cancer Endocrine-Related nuclear receptors can potentially drive similar transcriptional responses to the androgen receptor, while analysis of expression and sequencing databases shows disproportionately high mutation and copy number variation rates among the superfamily. Hence, the nuclear receptor superfamily is of intense interest in the drive to understand how prostate cancer recurs and how we may best treat such recurrent disease. This review aims to provide a snapshot of the current knowledge of the roles of different nuclear Endocrine-Related Cancer receptors in prostate cancer – a rapidly evolving field of research. (2016) 23, T85–T108 Introduction Prostate cancer is initially an androgen-dependent easily passing through biological membranes and disease, and inoperable cases are treated using hormone modifiable by drug design, they potentially represent therapy including androgen ablation (downregulation highly ‘druggable’ targets for therapy: in 2006, 13% of of androgen production and steroid synthesis inhibitors) all FDA-approved drugs targeted NRs (Overington et al. and antiandrogens that act at the level of the androgen 2006). Members of the NR superfamily are involved in receptor (AR). The AR is a ligand (androgen)-activated the sensing of environmental and metabolic cues such transcription factor and a member of the nuclear as hormones, dietary factors and sunlight and thence receptor (NR) transcription factor superfamily. There in the regulation of key pathways regulating cellular are 48 members in this superfamily in humans, and survival, proliferation, differentiation, homeostasis although not all are associated with ligands because and metabolism (Robinson-Rechavi et al. 2003). many NRs bind to and are activated by small molecules The superfamily is commonly broken down, based on http://erc.endocrinology-journals.org © 2016 Society for Endocrinology This paper is part of a special section on Celebrating Women in Cancer Research. DOI: 10.1530/ERC-16-0319 Published by Bioscientifica Ltd. The Guest Editors for this section were Charis Eng and Deborah Marsh. Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 10:52:30AM via free access 10.1530/ERC-16-0319 Thematic Review D A Leach et al. Nuclear receptors in 23:11 T86 prostate cancer either sequence homology or DNA-binding/dimeric (the mineralocorticoid receptor, MR) (Fig. 1A). They are partner specificity (Figs 1B and 2A), into 3 or 4 groups encoded by genes usually consisting of 8 exons and have that include (i) the steroid receptors, (ii) the obligate a modular structure with 4 main functional domains, heterodimeric partners of retinoid receptors, which reflected in the exon/intron organisation of the gene. includes retinoic acid/thyroid hormone receptors These are (i) the N-terminal domain, which contains and (iii) so-called ‘orphan’ receptors for which no transcriptional activation function(s) and interacts with endogenous ligand has been identified (although given cofactors: this is highly variable in length, shows little that for many receptors previously termed orphans conservation or structure and is encoded by a single exon. ligands have been found, making them ‘adopted (ii) The DNA-binding domain (DBD): this is encoded by 2 orphans’, the existence of endogenous ligands cannot exons, each of which encodes a single zinc-finger-like motif be ruled out). Orphan receptors can be subdivided and is the most highly conserved region. (iii) The ‘hinge’ into those that bind DNA as dimers and those that region: this often contains a nuclear localisation signal bind as monomers. Although different categorisation and in some (notably the thyroid and retinoic) receptors, systems are not directly comparable, these are broadly has a role in transcriptional silencing; it is of variable size accepted categories (Mangelsdorf et al. 1995, Nuclear and poorly conserved. (iv) The ligand-binding domain Receptors Nomenclature 1999, Robinson-Rechavi et al. (LBD): as well as containing the ligand-binding pocket, 2003). Here, the receptors are discussed within broadly this is involved in dimerization, transcriptional regulation functional groupings. (it contains another activation function) and interactions Nuclear receptors range in size from a little over 400 with heat-shock proteins and cofactors; it is encoded by 5 amino acids (COUPTF, vitamin D receptor) to almost 1000 exons and is relatively well conserved both in sequence and Endocrine-Related Cancer Endocrine-Related Figure 1 Schematic diagrams of nuclear receptor structures and DNA binding. (A) Representative images of different nuclear receptor (NR) types, comparing their overall size and highlighting the amino, N-terminal domain (NTD), the DNA-binding domain (DBD) and ligand-binding domain (LBD). The AR is used as an example to highlight these regions, as well as the AF1 and AF2 sites. (B) NRs interact with DNA in pairs, with either the same NR (homodimer) or another NR (heterodimer), or bind singularly as a monomer. Each NR has a specific mode of binding resulting in gene transcription. http://erc.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-16-0319 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 10:52:30AM via free access Thematic Review D A Leach et al. Nuclear receptors in 23:11 T87 prostate cancer structure, containing 11 or 12 alpha-helices that realign machinery, remodelling chromatin, modifying histone upon ligand binding to form coregulator-binding surfaces proteins and enzymes or acting as chaperones (Chmelar (Mangelsdorf et al. 1995, Wurtz et al. 1996, Robinson- et al. 2007, Jia et al. 2008). Further, their effects on gene Rechavi et al. 2003). Every NR achieves its transcriptional transcription appear to be gene specific and cell lineage/ effects in concert with a number of coregulator proteins. differentiation state specific. These comprise coactivators, which increase the activity Although androgen ablation and antiandrogens are of the receptor and in general are recruited to the very effective initially in prostate cancer treatment, it is activated, ligand-bound receptor, and corepressors, which almost inevitable that resistance will eventually occur and decrease receptor activity and may be recruited in the men progress to advanced, castration-resistant prostate absence of ligand or presence of inhibitory ligands cancer (CRPC). This stage was once termed ‘androgen (antagonists) (Bevan & Parker 1999, McKenna & O’Malley independent’, but this was felt to be misleading because 2002). The list of coregulators is ever expanding, with although the tumours recur in low androgen conditions, hundreds reported to date (Heemers & Tindall 2007). The the majority remain dependent on the AR signalling methods by which coregulators affect AR action are diverse pathway for growth. The mechanisms by which the AR and include promoting the recruitment of transcriptional axis is activated in these tumours include amplification Endocrine-Related Cancer Endocrine-Related Figure 2 Nuclear receptor alterations in prostate cancer. (A) List of 48 nuclear receptors (NR) grouped based on their cognate ligands. (B)TCGA data of copy number alterations (CNA) of all NRs in prostate cancer samples. (C) TCGA data of mutations detected in all NRs in prostate cancer samples. (D) Pie chart demonstrating the incidence of mutations and CNAs in NRs for each NR group. http://erc.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-16-0319 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 10:52:30AM via free access Thematic Review D A Leach et al. Nuclear receptors in 23:11 T88 prostate cancer or increased expression of the AR leading to increased NR2E1, or TLX (8% of patients). When we evaluate AR protein and sensitivity to low or weak androgens; the aforementioned groups (Fig. 1D), of a total of 1387 mutations
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